Tasteless pharmaceutical composition and process



United States Patent 1 3,140,233 TASTELESS PHARMACEUTICAL COMPOSITIONAND PROCESS Peter Rieckmann, Mannheim-Waldhof, Germany, assignor to C.F. Boehringer & Soelme G.m.b.H., Mannheim-Waldhof, Germany, acorporation of Germany No Drawing. Filed Apr. 19, 1962, Ser. No. 188,901Claims priority, application Germany July 21, 1959 Claims. (Cl. 16782)The present invention relates to a process of producing tastelesspharmaceutical compositions and more particularly to a process of usingthe cetyl sulfate of the fi-dimethyl amino ethyl ether of (Z-methylphenyl) benzylalcohol, for producing tasteless pharmaceuticalcompositions, and compositions containing same.

The present application is a continuation-in-part of copendingapplication Serial No. 43,746, filed July -19, 1960, and entitledWater-Insoluble Salts of Basic Antihistaminic Compounds, and Process ofMaking Same.

It is of considerable importance in therapy, and especially in pediatry,to make administration of a pharmaceutical agent as easy as possible forthe patient. This may be a rather decisive factor in achievingsatisfactory results in psychiatry, where the patient should not becomeaware of receiving a drug.

In a number of instances, however, it has been found A impossible toneutralize completely the intensely bad and disagreeable taste ofpharmaceutical compounds by the addition of taste-correcting agents. Aconventional 3,140,233 Patented July 7, 1 964 ice effective because theyare rapidly and completely split erty renders the salt especiallysuitable for certain kinds of drug preparations. Ondissolving the saltin an organic solvent which is miscible with water, for instance, 'inethyl alcohol and pouring the resulting solution in Water,

'the acid addition salt of the antihistaminic compound is precipitatedin the form of a stable emulsion so that addition of an emulsifier isnot necessary. The resulting emulsion is tasteless. Due to this propertythe new salt can readily be used in the form of preparations to beapplied by means of medicine droppers and as juices.

The acid addition salt according to the present invention can beprepared according to known methods by reacting the water-soluble saltsof the ,B-dimethylamino ethyl ether of (Z-methylphenyl) benzylalcohol,for instance, its hydrochloride, with the alkali metal salts of the acidcetyl ester of sulfuric acid in an aqueous solution. It is also possibleto react said' antihistaminic compound with the free cetyl sulfuric acidin a suitable organic solvent and to distill off the solvent.

The following examples serve to illustrate thepreparation of the newcetyl sulfate without, however, limiting the same thereto:

method of improving the taste of pharmaceutical compounds consists inproviding water-insoluble derivatives thereof. These derivatives mustmeet with the following conditions:

The water-soluble salts of basic antihistaminic compounds, inparticular, have a very bitter, harsh, and tart taste and exert ananesthesizing effect. Attempts have been made to eliminate thedisagreeable taste of basic antihistaminic compounds by converting theminto their insoluble salts. Such almost insoluble salts are the acidaddition salts of fatty acids of high molecular weight and thesalicylates. However, these compounds are not completely free of adisagreeable taste. Salts of basic antihistaminic compounds with tannicacid have also been prepared (German Patent No. 1,001,455). However,such salts can be obtained in a pure state only with some difiiculties.Furthermore, tannic acid, which is split off in the gastro-intestinaltract, is certainly not inert.

It is one object of the present invention to provide pharmaceuticalcompositions, containing as active agent, the substantially tastelesswater-insoluble cetyl sulfate of the B-dimethylamino ethyl ether of the(2-methyl phenyl) benzylalcohol.

Another object of the present invention is to provide such compositionswhich may contain other drugs.

These and other objects of the present invention and advantageousfeatures thereof will become apparent as the description proceeds.

According to the present invention it has been found that compositionswhich contain the cetyl sulfate of B- dirnethylamino ethyl ether of the(2-methyl phenyl) benzylalcohol are substantially tasteless and arehighly Example 1 V 30.55 g. of the hydrochloride of the B-dimethylaminoethyl ether of (2-methyl phenyl) benzylalcohol are dissolved in aboutten times its amount of cold water. 34.4 g. of sodium cetyl sulfate aredissolved in about ten times its amount of hot water. Both solutions arecombined while stirring. A white oil precipitates which accumulates ,atthe bottom-of the vessel and solidifies, after standing for some time ina refrigerator. The supernatant liquid is poured ofl. The solid cake istriturated with cold water and washed, until free of sodium chloride, ona Buechne'r funnel. The resulting salt is dried in a vacuum at roomtemperature. Melting point: 43-45 C.

. Analysis.-Found:- 68.00% C.; 9.51% H; 5.6% S; 2.1l%'N. Calculated:68.99% C.; 9.71% H; 5.42% S; 2.37% N (N determined by the Kjeldahlmethod: 2.25%

The'stoichiometric content of base in said salt is 45.57%. A content of45.3% was calculated from the ultraviolet absorption at 259 mp.

' Example 2 26.9 g. of the fi-dimethylamino ethyl ether of (2 methylphenyl) benzylalcohol are dissolved in 200 cc. of carbon tetrachloride.The solution is mixed with a "solution of 32.2 g. ofcetyl sulfuric acidin 300 cc. of carbon tetrachloride; After evaporation of the solvent thecetyl sulfate of Example 1 is obtained.

- In place of the sodium salt, theremay be employed the potassium saltor other alkali metal salts of said acid ester.

In place of the hydrochloride of the antihistaminic ba'se,there may beused other Water soluble acid addition salts, such as the hydrobromides,phosphates, maleates, succinates.

In place of carbon tetrachloride used 'as solvent for the antihistaminicbase and cetyl sulfuric acid, there may be employed othersolventswherein the base as well as the cetyl sulfate is soluble,-such aschloroform, methylene chloride, methanol, ethanol, acetone. I

As stated above, the new acid addition salt is characterized by itsextreme insolubility in water, so that it is absolutely tasteless; byits rapid cleavage in the gastrointestinal tract so that'itexertsits'antihisaminic acivity shortly after administration; by itspropery of yielding on cleavage, in addition to the antihistaminicagent, substantially nontoxic, well tolerated degradation products; andby its high solubility in organic solvents such as ethanol.

The new acid addition salt is administered in the form of solid shapedpreparations such as tablets, pills, dragees, and the like, or in theform of aqueous emulsions and emulsions in sugar sirup, fruit juices,and the like, which do not require the addition of emulsifying agents.

Especially valuable pharmaceutical compositions of the cetyl sulfateaccording to the present invention are obtained, for instance, bycombining the same with reserpine. Such a composition of the cetylsulfate of the fi-dimethylamino ethyl ether of (2-methyl phenyl)benzylalcohol and reserpine has proved to be an excellent psychotropicagent useful in many disorders such as vegetative and neurocirculatorydystonias, climacteric, preclirnacteric, and pregnancy disorders, andmany others.

It is frequently of importance to administer such compositions in liquidform. This is not possible when using the fl-dimethylamino ethyl etherof (Z-methyl phenyl) benzylalcohol as such or in the form of itshydrochloride because the bitter taste of these compounds prevents itsuse. In such instances the combination of reserpine with the cetylsulfate of said ether has proved of special advantage.

The following example illustrates such compositions without, however,being limited thereto.

Example 3 1 g. of the di-sodium salt of ethylene diamine tetraaceticacid is dissolved in 100 cc. of distilled water. The resulting solutionis added to 50 l. of 96% ethanol. 50 g. of a mixture of 2,5-di-tertiarybutyl-4-methyl phenol, ascorbyl palmitate and citric acid, sold underthe trademark Oxynex 2004 by the firm E. Merck of Darmstadt, Germany, 53g. of monocetyl sulfate, and 100 g. of reserpine are successively addedthereto while stirring. Solution is achieved by heating of 50 C. withstirring. 30 kg. of polyethylene glycol 300 and finally 9.670 kg. of thecetyl sulfate of the B-dimethylamino ethyl ether of (Z-methyl phenyl)benzylalcohol obtained according to Example 1 or 2 are admixed theretowhile stirring and the mixture is filled up to a volume of 100 liters bythe addition of 96% ethanol. The resulting solution is a substantiallytasteless preparation which contains 1 mg. of reserpine and 96.7 mg. ofthe cetyl sulfate of the B-dimethylamino ethyl ether of (2-methylphenyl) benzylalcohol (corresponding to 50 mg. of said base) per cc.,Le. 40 drops.

Mono-cetyl sulfate is added to prevent splitting up of the cetyl sulfateof the p-dimethylamino ethyl ether of (2-methyl phenyl) benzylalcohol bythe reserpine base. Addition of said mono-cetyl sulfate thus is ofconsiderable importance in the preparation of stable liquidcompositions.

Such a liquid composition is preferably administered by adding 5 dropsto 30 drops thereof into tea or other liquids, depending on theseriousness of the symptoms. Administration is repeated three timesdaily. The effective single dose thus is between about 0.2 mg. and about0.75 mg. of reserpine and between about 6.2 mg. and about 27.5 mg. ofthe ether base (in the form of its cetyl sulfate) while the effectivedaily dose is between about 0.6 mg. and about 2.25 mg. of reserpine andbetween about 18.6 mg. and about 82.5 mg. of the ether base (in the formof its cetyl sulfate).

The preferred solvent is the mixture of polyethylene glycol and ethanolused in Example 3. Other non-toxic solvents and solvent mixtures may, ofcourse, also be used.

Due to the insolubility of the cetyl sulfate of fl-dimethyl aminoethylether of (2-methyl phenyl) benzyl alcohol in water or aqueous liquidssuch as tea and the like and its capability of being readily anduniformly emulsified therein, the composition is substantially tastelessand thus free of the disadvantages of the bitter tasting Water-solublesalts of said basic ether and of their unwanted anesthetizing effects.

Such compositions, furthermore, are substantially free of theundesirable side-effects observed on administration of reserpine alone,such as bradycardia and excessive hypotension, disturbances of thevoluntary nervous system such as Parkinsons symptoms andhypersalivation, and of the autonomic nervous system, such as diarrhea,edema, pains in the limbs While the sedative effect of reserpine is notreduced but actually increased.

I claim:

1. In a process of producing a substantially tasteless pharmaceuticalcomposition, the steps which comprise dissolving the cetyl sulfate ofthe ,B-dimethylamino ethyl ether of (Z-methyl phenyl) benzyl alcohol ina substantially non-toxic, watermiscible organic solvent and adding theresulting solution to a drinkable aqueous liquid, thereby forming anemulsion of said cetyl sulfate in said liquid.

2. The process according to claim 1, wherein the organic solvent is amixture of polyethylene glycol and ethanol.

3. In a process of producing a substantially tasteless pharmaceuticalcomposition, the steps which comprise dissolving reserpine andmono-cetyl sulfate in ethanol, adding thereto polyethylene glycol andthe cetyl sulfate of the ,B-dimethylamino ethyl ether of (Z-methylphenyl) benzyl alcohol, and stirring said mixture to cause dissolutionof the components.

4. In a process of producing a substantially tasteless pharmaceuticalcomposition, the steps which comprise dissolving reserpine andmono-cetyl sulfate in a substantially non-toxic, water-miscible, organicsolvent, adding thereto the cetyl sulfate of the fl-dimethylamino ethylether of (Z-methyl phenyl) benzyl alcohol, and stirring said mixture tocause dissolution of the components.

5. In a process of producing a substantially tasteless pharmaceuticalcomposition, the steps which comprise dissolving reserpine andmono-cetyl sulfate in ethanol, adding thereto polyethylene glycol andthe cetyl sulfate of the B-dimethylamino ethyl ether of (2-rnethylphenyl) benzyl alcohol, stirring said mixture to cause dissolution ofthe components and adding the resulting solution to a drinkable aqueousliquid, thereby forming an emulsion of said cetyl sulfate in saidliquid.

6. In a process of producing a substantially tasteless pharmaceuticalcomposition, the steps which comprise dissolving reserpine andmono-cetyl sulfate in a substantially non-toxic, water-miscible, organicsolvent, adding thereto the cetyl sulfate of the fi-dimethylamino ethylether of (2- methyl phenyl) benzyl alcohol, stirring said mixture tocause dissolution of the components, and adding the resulting solutionto a drinkable aqueous liquid, thereby forming an emulsion of said cetylsulfate in said liquid.

7. A substantially tasteless pharmaceutical composition comprising asolution of the cetyl sulfate of the [3- dimethylamino ethyl ether of(Z-methyl phenyl) benzylalcohol in a substantially non-toxic,water-miscible organic solvent.

8. A substantially tasteless pharmaceutical composition comprising asolution of the cetyl sulfate of the fl-dimethylamino ethyl ether of(Z-methyl phenyl) benzylalcohol in a mixture of polyethylene glycol andethanol.

9. A substantially tasteless pharmaceutical composition comprising asolution of reserpine, mono-cetyl sulfate, and the cetyl sulfate of thefl-dimethylamino ethyl ether of (2-methyl phenyl) benzylalcohol in asubstantially non-toxic, water-miscible organic solvent.

10. A substantially tasteless pharmaceutical composition comprising asolution of reserpine, mono-cetyl sulfate, and the cetyl sulfate of theB-dimethylamino ethyl ether of (2-methyl phenyl) benzylalcohol in amixture of polyethylene glycol and ethanol.

No references cited.

1. IN A PROCESS OF PRODUCING A SUBSTANTIALLY TASTELESS PHARMACEUTICALCOMPOSITION, THE STEPS WHICH COMPRISE DISSOLVING THE CETYL SULFATE OFTHE B-DIMETHYLAMINO ETHYL ETHER OF (2-METHYL PHENYL) BENZYL ALCOHOL IN ASUBSTANTIALLY NON-TOXIC, WATERMISCIBLE ORGANIC SOLVENT AND ADDING THERESULTING SOLUTION TO A DRINKABLE AQUEOUS LIQUID, THEREBY FORMING ANEMULSION OF SAID CETYL SULFATE IN SAID LIQUID.